Skin ailments affect millions of people worldwide and cost billions of dollars in treatment costs. While the causes of skin ailments can come from many sources, exposure to ultraviolet (UV) and solar radiation is a common cause to many skin ailments.
Continued exposure to UV and solar radiation can directly damage DNA, generate reactive oxidants that peroxidize lipids, and damage other cellular components. UV and solar radiation can also initiate inflammation and suppress the immune response. The effects of such damage include changing the elasticity and content of skin, accelerating the aging of skin (dermatobeliosis), and causing raised, reddish, rough-textured growths (keratoses). U.S. Pat. No. 6,079,415. In some cases, too much sun exposure causes skin cells to develop into tumorous growths, which can then become skin cancer. Additional skin ailments include erythema, epidermolysis bullosa simplex, and the effects of aging, such as wrinkles, sagging skin, dry skin, age spots, and fine lines.
It is now widely accepted that UV radiation is the main factor responsible for the majority of nonmelanoma skin cancers. UV radiation is probably the most ubiquitous environmental carcinogen and the principal factor contributing to nonmelanoma skin cancers. At least three different effects of exposure to UV radiation contribute to the process of carcinogenesis in the skin: (i) direct DNA damage leading to the formation of DNA photoproducts, e.g., clycobutane-pyrimidine dimers and pyrimidine-pyridmidine products, (ii) oxidative stress-related DNA damage resulting from the formation of reactive oxygen intermediates, and (iii) immunosuppression that raises tolerance to genetic instability. See Setlow et al. J. Mol. Biol. (1966) vol. 17, pp. 237-54; Sander et al. Int. J. Dermatol. (2004) vol. 43, pp. 326-35; and Nishigori et al. J. Investig. Dermatol. Symp. Proc. (1996) vol. 1, pp. 143-46.
Skin cancer incidence is steadily rising and has reached epidemic proportions. The average rise in new skin cancer diagnoses has been 3-8% per year since the 1960's and nonmelanoma skin cancers are now the most common types of cancer in the United States, with over 1 million new cases per year. Alam et al. N. Engl. J. Med. (2001) vol. 344, pp. 975-83. See also WO 2006/118941.
Many types of chemoprotectors against cancer evoke large inductions of phase II enzymes of xenobiotic metabolism and increase glutathione levels in animal tissues. See Talalay et al. Toxicol. Lett. (1995) vol. 82/83, pp. 173-79. These cellular responses accelerate the detoxication of electrophiles and reactive forms of oxygen, and thereby protect cells against mutagenesis and neoplasia. Substantial evidence suggests that induction of these detoxication enzymes provides a major strategy for achieving protection against malignancy. See Talalay et al., supra. Phase II enzymes include Quinone reductase (NAD(P)H:oxidoreductase), Gluthathione S-transferases, and Glucuronosyltransferases. Additional phase II enzymes are described in U.S. Patent Application Publication No. 2005/0063965, hereby incorporated by reference in its entirety for all purposes. See e.g., pg. 4, para. [0046].
One strategy of fighting cancer is to invoke the activity of phase II enzymes through their inducers. Inducers include monofunctional inducers such as diphenol, thiocarbamate, 1,2-dithiol-3-thiones, and isothiocyanates. Sulforaphane (4-methylsulfinylbutyl isothiocyanate) and its analogs, described by U.S. Patent Application Publication No. 2005/0063965, incorporated here by reference in its entirety for all purposes, are illustrative examples of phase II enzyme inducers.
Isothiocyanates are found in various plants, including those from the Brassicae family and comprising broccoli, cauliflower, kale, brussel sprouts, arugula, cabbage, Chinese cabbage, collards, crambe, daikon, kohlrabi, mustard, red radish, turnip, and watercress. Isothiocyanates are generally produced when their precursors, glucosinolates, (β-thioglucoside N-hydrosulfate), are hydrolyzed by the enzyme myrosinase (β-thioglucoside glucohydrolase). In the plants described, glucosinolate and myrosinase are kept separate. This is possibly to prevent premature hydrolysis of glucosinolates into isothiocyanates.
Formulations comprising glucosinolates and myrosinase in separated form is desired to treat and prevent skin ailments as well as other cancerous conditions.